Exparel vs. Bupivacaine Hydrochloride vs. Placebo for Hernia Repair

NCT ID: NCT03541941

Last Updated: 2021-10-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 164 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-03
• Study Completion Date: 2019-12-19

Brief Summary

Patients usually experience some level of pain after their hernia repair. To control pain after the operation, surgeons have many options. One of them is to make some injections of pain blocker medications into the nerves that are responsible for the sensations the abdominal wall.This procedure is called TAP block (transversus abdominis place block). These medications are called local anesthetics, and there is a variety of medications that can be used. One of such medications is called Exparel® (Liposomal Bupivacaine). Exparel® has the potential benefit of lasting more hours than regular anesthetics. Although this drug is being used with increasing frequency, the investigators do not have good quality studies investigating the benefits of using this medication during a hernia repair, especially when compared to other types of local anesthetics (Bupivacaine Hydrochloride) or when compared to not injecting this medication at all. This study aim to investigate if Exparel®, when injected in the nerves of the abdominal wall during hernia repair can: (1) reduce the dose of additional opioid medications (morphine and similar) needed to achieve good pain control and (2) result in lower pain scores. The hypothesis is that Exparel® will result in a 30% decrease in the total requirements for opioid medications during the first 72 hours after surgery. Patients will be randomized to receive either Exparel®+Bupivacaine Hydrochloride, Bupivacaine Hydrochloride or Placebo (normal saline) during the operation through a TAP block. All patients will receive a patient controlled analgesia device after the operation, where patients can simply push a button every time they feel pain and the device will administer a dose of opioid medications. The investigators of the study will record the necessary amount of opioids used by the patients to achieve good pain control and also record pain scores several times during hospital stay.

Detailed Description

This will be a double-blind, 3-arm, randomized controlled trial with a treatment 1: treatment 2: control allocation ratio of 1:1:1. Primary outcomes of interest are opioid requirements and pain scores over initial 72 hours of the postoperative period. Opioid requirements will be assessed by measuring the cumulative dose of opioids administered intravenously (infused through a patient-controlled analgesia device as well as the quantity of opioids administered intravenously as rescue, if needed) and the quantity of opioids administered through oral preparations. This will be assessed at time points: while patients are at the post-anesthesia care unit (PACU), at postoperative days 1(24h±4 hours), 2(48h±4 hours), 3(72h±4 hours) and at the date of hospital discharge. The total dose of opioids used at each time point will be recorded and converted into morphine equivalents for standardization and analysis. The cumulative dose of opioids from 0 hours to 72 hours after the operation and for the total hospital length of stay will be recorded. In addition, the dose of opioids administered intra-operatively by the anesthesiologist, time for first oral opioid dose over the first 72 hours (discontinuation of PCA), and the percentage of patients not requiring opioids over the first 72 hours will also be recorded.

Pain scores will be determined using a 100mm visual analog scale (VAS). The VAS is a 100mm horizontal line with two endpoints: 0 (no pain) and 100 (worst imaginable pain). Pain scores will be assessed at baseline during preoperative evaluation, at the PACU, at postoperative days 1(24h±4 hours), 2(48h±4 hours), 3(72h±4 hours), and at the time of hospital discharge.

Additional pain scores will be obtained using the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Intensity 3a survey at baseline and 30-day follow-up. This survey will be completed by patients in person during enrollment and 30-day follow-up. Secondary outcomes of interest include the length of hospital stay and Patient-Reported Quality of Life (PRQOL). Both information is already routinely collected through the Americas Hernia Society Quality Collaborative (AHSQC). Length of hospital stay will be recorded in days. PRQOL will be assessed using the Hernia-Related Quality-of-Life survey (HerQLes). The HerQLes is a 12-item, validated, hernia-specific survey that assesses quality of life through abdominal wall function after ventral hernia repair. HeQLes scores will be assessed at baseline and 30 days after the operation.

All patients will undergo the same operation, under a standard of care protocol. Skin preparation, hair removal, perioperative antibiotics and venous thromboembolism prophylaxis will be performed per Surgical Care Improvement Project protocol guidelines. The procedure will be performed through a midline incision. Upon entering the abdominal cavity, all adhesions between intra-abdominal contents and the anterior abdominal wall are routinely lysed using sharp dissection. When present, hernia contents are reduced back to the cavity. At the end of adhesiolysis, the surgeon will ask the OR nurse to contact the investigational pharmacy via telephone, who will randomize the subject. The investigational pharmacy will be responsible for preparing and dispensing the assigned intervention. The OR nurse will receive the drug from the investigational pharmacy in a standardized bag and will dispense it to the surgeon at the time of the TAP block. Neither the surgeon nor other members of the surgical team will be informed about which of the interventions were assigned to the specific patient. Electronic medical records will contain the information: "Patient was randomized and assigned to receive intervention according to randomization performed by investigational pharmacy." Retromuscular hernia repair is performed initially incising the posterior rectus sheath just lateral to the linea alba. The release will be performed at least 5 cm above and below the fascial defect, and retrorectus dissection is carried out laterally in the direction of the linea semilunaris. If deemed necessary, a posterior component separation will be performed by incising the posterior lamella of the internal oblique, dividing the fibers of the transversus abdominis muscle and dissecting the preperitoneal and retroperitoneal spaces of the lateral abdominal wall laterally.

At the end of the myofascial release, randomization will occur and the assigned intervention drug will be dispensed in syringes to the surgeon who will perform the perform a TAP block under direct visualization. Patients will be randomized using a computer-generated random allocation sequence, by the investigational pharmacy personnel.

Injections of the designated drug (group 1, 2 or 3) will be performed under direct visualization by the attending surgeon, in 5 vertical levels, to the thoracoabdominal nerves (from T7 to T11).

The interventions are:

• Treatment 1- Administration of a solution of Exparel® combined with Bupivacaine Hydrochloride 0.25% and normal saline, through a bilateral TAP block performed intraoperatively by the attending surgeon, during open ventral hernia repair;
• Treatment 2: Administration of a solution of Bupivacaine Hydrochloride 0.25% and normal saline, through a bilateral TAP block, performed intraoperatively by the attending surgeon, during open ventral hernia repair ;
• Control (Placebo): administration of normal saline through a bilateral TAP block performed intraoperatively by the attending surgeon, during open ventral hernia repair.

The posterior sheath will be reapproximated, and a standard piece of polypropylene mesh will be placed in the retromuscular space.

Mesh type will be defined by the surgeon intraoperatively according to the patient and hernia-specific variables. Mesh fixation will be performed circumferentially using mechanical sutures. Closed suction drains will be placed above the mesh and in the subcutaneous space, and the timing of removal will be based on the surgeon's standard practice. Fascial closure and management of wound dressings will also follow the surgeon's standard practice.

For postoperative analgesia, all patients will also receive a patient-controlled analgesia (PCA) device according to the standard of care; preferably:

• Hydromorphone HCL 0.5mg/ml (Dilaudid®, Purdue Pharmaceuticals, Stamford, CT) in 100ml of normal saline, with no basal rate infusion, a patient bolus dose of 0.2-0.4mg, bolus interval of 6 minutes (maximum 10 doses per hour).

To ensure the comfort and adequate pain postoperative pain control, additional intravenous or oral opioids are allowed in the protocol, to be administered for breakthrough pain (as needed). Subjects should only receive rescue medication upon request, and for pain control.

Estimated patient accrual time is 2 years with data collection to occur over 30 days from randomization of each patient. Data analysis and manuscript production will occur within 6 months of the completion of data collection.

As with any surgical procedure, patients may experience pain, bleeding, and discomfort. Common occurrences following hernia repair include seroma, hematoma, inflammation, wound dehiscence, and infection. Risks of Bupivacaine Hydrochloride include allergic reactions, arrhythmias, chest pain or pressure, dizziness, confusion, restlessness, tinnitus, blurred vision, dyspnea, seizures, nausea, emesis, and lethargy. Risks of Exparel® include nausea, vomiting, constipation, as well as (rarely) seizures and cardiac arrest. Patients receiving placebo intraoperatively will not necessarily experience higher levels of pain, as all individuals, regardless of intervention arm, will be provided a multimodal pain management regimen with patient-controlled analgesia postoperatively. There are no direct benefits to subjects for participation in this study. Subject participation will, however, help physicians and hospital administrators better understand the outcomes of Exparel® use concerning postoperative pain management and its influence on opioid consumption, hospital length of stay and quality of life. Patients are under no obligation to participate in this study. A member of the research team will discuss all available surgical options with patients. It will be emphasized that refusal to participate in this study will not impact any patient's ability to receive surgical care. There will be no payment for the subjects for the participation in this study.

Conditions

Analgesia, Postoperative

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Exparel

Solution of 266mg of Exparel + 150mg Bupivacaine HCL + 40cc normal saline= 120cc administered through a transversus abdominis plane block performed intraoperatively by the surgeon under direct visualization

Group Type: EXPERIMENTAL

Exparel

Intervention Type: DRUG

Solution of: 266mg of Bupivacaine Liposome Injectable Suspension (Exparel) mixed with 150mg of Bupivacaine Hydrochloride 0.25% expanded with 60cc of Normal Saline (Nacl0.9%) administered intraoperatively through a transversus abdominis plane (TAP) block

Bupivacaine Hcl 0.25% Inj

Intervention Type: DRUG

Solution of: 150mg of Bupivacaine Hydrochloride 0.25% expanded with 60cc of Normal Saline (Nacl0.9%) administered intraoperatively through a transversus abdominis plane (TAP) block

Bupivacaine Hcl 0.25% Inj

Solution of 150mg Bupivacaine HCL expanded with 60cc of normal saline=120cc administered through a transversus abdominis plane block performed intraoperatively by the surgeon under direct visualization

Group Type: ACTIVE_COMPARATOR

Bupivacaine Hcl 0.25% Inj

Intervention Type: DRUG

Solution of: 150mg of Bupivacaine Hydrochloride 0.25% expanded with 60cc of Normal Saline (Nacl0.9%) administered intraoperatively through a transversus abdominis plane (TAP) block

Placebo

120 cc of normal saline administered through a transversus abdominis plane block performed intraoperatively by the surgeon under direct visualization

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Normal saline administered intraoperatively through a transversus abdominis plane (TAP) block

Interventions

Exparel

Solution of: 266mg of Bupivacaine Liposome Injectable Suspension (Exparel) mixed with 150mg of Bupivacaine Hydrochloride 0.25% expanded with 60cc of Normal Saline (Nacl0.9%) administered intraoperatively through a transversus abdominis plane (TAP) block

Intervention Type: DRUG

Bupivacaine Hcl 0.25% Inj

Solution of: 150mg of Bupivacaine Hydrochloride 0.25% expanded with 60cc of Normal Saline (Nacl0.9%) administered intraoperatively through a transversus abdominis plane (TAP) block

Intervention Type: DRUG

Placebo

Normal saline administered intraoperatively through a transversus abdominis plane (TAP) block

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patients with Primary Ventral or Incisional Hernias
• Scheduled to undergo hernia repair through an open approach
• Hernia repair performed in an elective setting
• Hernia repair performed through a midline incision
• Hernia repair performed in a clean wound
• Hernia repair performed with mesh placed in the retromuscular position

Exclusion Criteria

• patients with less than 18 years old of age
• patients scheduled to undergo a minimally invasive hernia repair
• patients where hernia repair is planned to be performed with mesh placement in a different position than retromuscular
• patient undergoing hernia repair with a clean-contaminated, contaminated or infected wound
• patients undergoing hernia repair in an non-elective fashion
• patients with allergy, hypersensitivity or contraindication to bupivacaine
• patients with history of chronic liver disease with moderate or severe impairment in liver function defined as a Child-Pugh class B or C
• patients with chronic kidney disease on dialysis
• chronic opioid users, defined as daily or near daily use of opioids for at least 90 days in the past year
• patients unable to provide informed written consent

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pacira Pharmaceuticals, Inc

INDUSTRY

Sponsor Role: collaborator

The Cleveland Clinic

OTHER

Sponsor Role: lead

Responsible Party

Michael Rosen

Staff Surgeon

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael J. Rosen, MD

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Locations

Cleveland Clinic Comprehensive Hernia Center

Cleveland, Ohio, United States

Countries

United States

References

Fafaj A, Krpata DM, Petro CC, Prabhu AS, Rosenblatt S, Tastaldi L, Alkhatib H, Tu C, Zolin SJ, Thomas JD, Costanzo AM, Rosen MJ. The Efficacy of Liposomal Bupivacaine on Postoperative Pain Following Abdominal Wall Reconstruction: A Randomized, Double-blind, Placebo-controlled Trial. Ann Surg. 2022 Aug 1;276(2):224-232. doi: 10.1097/SLA.0000000000004424. Epub 2020 Dec 2.

Reference Type: DERIVED

PMID: 33273351 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

18-133

Identifier Type: -

Identifier Source: org_study_id